PPARα Agonists Suppress Osteopontin Expression in Macrophages and Decrease Plasma Levels in Patients With Type 2 Diabetes

Nakamachi, Takafumi; Nomiyama, Takashi; Gizard, Florence; Heywood, Elizabeth B.; Jones, Karrie L.; Zhao, Yue; Fuentes, L.; Takebayashi, Kohzo; Aso, Yoshimasa; Staels, Bart; Iwamoto, Toshihiko; Bruemmer, Dennis

doi:10.2337/db06-1177

Cited by 75 publications

(78 citation statements)

References 37 publications

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“…PPAR-g agonists inhibit TGF-b1-CTGF signaling, OPN expression, and the activity of MMP-2 and MMP-9. 6,7,37,38 On the other hand, ARBs usually inhibit TGF-b1-CTGF signaling and OPN activity, but do not affect MMP-2 or MMP-9 activity. [39][40][41][42] Thus, Telmisartan is a unique ARB that possesses potent anti-fibrotic activity via inhibition of MMP activation, OPN expression and TGF-b1-CTGF signaling.…”

Section: Discussionmentioning

confidence: 99%

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-g (PPAR-g) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-g agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-g antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor b-1 (TGF-b1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-g and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-g and TIMP-1, and inhibition of TGF-b1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-g activation were suggested to be important in addition to suppression of Ang II activity. Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by hypertrophy associated with interstitial fibrosis of the noninfarcted myocardium, and causes LV dilatation and cardiac dysfunction. It is known that angiotensin II (Ang II) has a crucial role in the development of unfavorable LV remodeling, and recent studies based on animal experiments have demonstrated that treatment with an Ang-converting enzyme inhibitor (ACE-I) and/or Ang II type I receptor blocker (ARB) can attenuate unfavorable LV remodeling. 1,2 Moreover, other experimental studies suggested that activation of peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor, improves unfavorable LV remodeling after MI. [3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well ...

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Section: Discussionmentioning

confidence: 99%

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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“…Liver X receptor agonists inhibit cytokine-induced OPN expression in macrophages through interference with AP-1 signaling pathways. AP-1 regulation is further demonstrated in that OPN transcription is suppressed by PPAR-α agonist through repression of AP-1-dependent transactivation of the OPN promoter (Nakamachi et al, 2007). (Rollo et al, 2005).…”

Section: Signaling Pathwaysmentioning

confidence: 94%

Osteopontin: Role in immune regulation and stress responses

Wang¹,

Denhardt²

2008

Cytokine & Growth Factor Reviews

609

558

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“…7,8 Moreover, the OPN levels are particularly elevated in patients with type 2 diabetes, 9,10 and we showed that peroxisome proliferator-activated receptor a ligands suppress OPN expression in macrophages in vitro and that bezafibrate reduces plasma OPN levels in patients with type 2 diabetes. 11 These clinical studies provide evidence that OPN may play a causal role in the development of cardiovascular disease in humans.…”

mentioning

confidence: 95%

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

Tachibana¹,

Ogawa

Matsushita³

et al. 2012

Journal of the American Society of Nephrology

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Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

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PPARα Agonists Suppress Osteopontin Expression in Macrophages and Decrease Plasma Levels in Patients With Type 2 Diabetes

Cited by 75 publications

References 37 publications

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Osteopontin: Role in immune regulation and stress responses

Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

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